Potentially addictive drugs can have very different behavioral and subjective effects depending on the context in which they are experienced. That is, the effects of drugs are not only a function of their direct pharmacological actions but they are a function of complex interactions among their pharmacological actions, the state of the organism and the setting in which they are administered ("set and setting"). Therefore, to understand the long-term sequelae associated with drug use and abuse, including tolerance, sensitization, dependence and addiction, one must understand the nature of these drug-environment interactions. Almost nothing is known, however, about the neurobiological mechanisms by which environmental factors modulate drug actions. We have developed a simple animal model to explore these issues. We have found that the context in which psychomotor stimulant drugs (amphetamine or cocaine) are administered, whether it is at HOME or in a NOVEL environment, can have a profound effect on both their acute psychomotor activating effects and their ability to produce a form of drug experience-dependent neuroplasticity known as behavioral sensitization. Behavioral sensitization is a form of neurobehavioral adaptation implicated in addiction, whereby past drug exposure renders individuals hypersensitive to the psychomotor activating and incentive motivational effects of drugs. The purpose of experiments proposed here is to study the mechanisms by which environmental context modulates these actions of amphetamine and cocaine. In particular, during the past grant period we found that the ability of amphetamine and cocaine to induce the expression of the immediate early gene (IEG), c-fos, which is a reliable indicator of neuronal activation, is powerfully modulated by environmental context. This occurs in many brain regions, but the drug interaction is especially strong in brain regions that have been implicated in psychomotor activation and different aspects of drug reward, such as the dorsal and ventral striatum and the amygdala. Furthermore, the nature of the drug-environment interaction is such that the drugs engage different populations of striatal neurons depending on environmental condition. Psychostimulants induce c-fos mRNA in cells that are positive for enkephalin mRNA only when they are administered in a NOVEL environment. This suggests that the neural circuitry engaged by psychostimulant drugs varies as a function of the context in which they are administered. We propose here to use in situ hybridization histochemical techniques to further characterize how environmental context modulates the ability of amphetamine and cocaine to induce IEG expression in neurochemically-specific cell populations in the striatum, and the extent to which this is related to the ability of environmental context to facilitate the development of behavioral sensitization. We will also explore the consequences of past drug experience, and the environment in which drugs were experienced, on neurochemically-specific patterns of IEG expression seen upon re-exposure to these agents. These latter studies should provide new information about the neurobiological consequences of repeated exposure to amphetamine and cocaine, and how this varies as a consequence of environmental context.. In summary, these studies should provide new insights into how drug-environment interactions can so dramatically alter drug effects, including liability to forms of drug-induced plasticity that may contribute to addiction.